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Such factors as suspending medium, operating pressure, exposure time, inoculum size, and strain, sex, age, and weight of the animals were examined for their effects on the development of respiratory tract infection with Klebsiella pneumoniae DT-S in mice. The suspending medium was one of the most important factors. Aerosol challenge with a 10(9) colony-forming units per ml resulted in deposition of 10(4) colony-forming units of the organisms in the lung. The numbers of organisms in the lung increased rapidly, and by 30 h, a well-developed pneumonia was apparent. All the mice died within 4 days after infection. The therapeutic effectiveness of single-dose kanamycin regimens decreased markedly with a delay in administration. The effectiveness of multi-dose kanamycin regimens was influenced by the frequency of dosage. Thus a 12-h dosage schedule was superior to a 24-h regimen. Administration of 20 mg of kanamycin per kg at 12-h intervals for 10 days, initiated 30 h after infection, provided a complete cure. The infecting organisms in the lung, trachea, and blood were eradicated by the kanamycin therapy, but those in the nasal cavity were difficult to eliminate.

The activity of cefmenoxime (SCE-1365), 7 beta-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid, was compared with that of other cephalosporins. Cefmenoxime exhibited high activity against a wide variety of gram-positive and gram-negative bacteria. The in vitro activity of cefmenoxime against Streptococcus pyogenes, Haemophilus influenzae, and Enterobacteriaceae, including indole-positive Proteus, Serratia marcescens, Enterobacter cloacae, and Citrobacter freundii, was 10 to 1,000 times greater than that of several other cephalosporins. Against Pseudomonas aeruginosa, cefmenoxime showed activity two to four times that of sulbenicillin and carbenicillin but less than that of cefsulodin. Variation in pH, addition of horse serum, and type of growth medium had definite effects on the activity of cefmenoxime, and the inoculum size affected the activity against bacterial species. In Escherichia coli cefmenoxime showed marked affinity for penicillin-binding protein 3 (PBP-3), followed by PBP-1 (1A and 1B). This affinity profile was well correlated with its filamentous cell-forming activity under extremely low drug concentrations and with its bactericidal activity against microorganisms. The high in vitro activity of cefmenoxime was reflected in the degree of protection observed in mice infected intraperitoneally with a wide variety of gram-positive and gram-negative bacteria. Furthermore, cefmenoxime showed good therapeutic activity against infection models in mice such as respiratory tract infection caused by Klebsiella pneumoniae and urinary tract infection caused by Proteus mirabilis.

The efficacies of several dosage schedules, productive of plasma levels of cefotiam and cefazolin of short and long duration and starting at three levels of cefotiam and cefazolin of short and long duration and starting at three different times (3, 18, and 30h) after infection, were examined in experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice. With each of the multiday regimens there was a large segment of the day when plasma levels fell below assayable concentrations. In all cases, cefotiam proved about eight times as active as cefazolin, indicating that the potent in vitro antibacterial activity of cefotiam was well reflected in the therapeutic effect in this model infection. As judged by the total dose administered, the regimen of cefotiam producing a low but sustained plasma level gave better therapeutic effects than that exhibiting a high but transient plasma level. The cefotiam levels in the plasma of mice that received the regimen effective when initiated at 18 h after infection were less than the expected levels in humans after intravenous infusion of the usual clinical dose.

The effect of cefotiam and cefazolin on the ultrastructure of Klebsiella pneumoniae DT-S in vitro and in experimental pneumonia in mice was examined by electron microscopy. The action of both cephalosporins against K. pneumoniae DT-S was bactericidal, and a dose response in the action was definite. At the minimal inhibitory concentration of each cephalosporin, filamentation of the cells was induced and the cytoplasm became sparse during the course of incubation. With elevation of the concentration of the cephalosporins, spheroplasts were formed; they subsequently collapsed. In the lungs of mice, the infecting organisms localized in the alveolar space, and each cell was connected by a threadlike material. A fibrous matrix, located on the cell surface of the infecting organisms, was observed in ultrathin sections. By administration of each cephalosporin to mice, several morphological changes, similar to those noted in vitro, were observed in the infecting organisms.